This invention relates generally to molecular medicine and, more specifically, to alternatively spliced prostaglandin FP receptors.
Prostaglandins (PG) and thromboxane, collectively named prostanoids, are oxygenated fatty acids that bind to seven transmembrane domain G-protein coupled receptors (GPCRs). The classification of prostanoid receptors into DP, EP, FP, IP, and TP is based on the binding and functional potency of the five naturally occurring prostanoids, PGD2, PGE2, PGF2α, I2, and TXA2, respectively. Prostanoid receptors have been cloned and expressed in cultured cells, where ligand binding and signal transduction properties have been studied. It is recognized that prostanoids can bind to more than one prostanoid receptor type; however, each prostanoid binds to its respective receptor with an affinity at least one order of magnitude higher than its affinity for the other four prostanoid receptors.
Prostanoids produce numerous physiologic and pathophysiologic effects and regulate cellular processes in nearly every tissue. The wide spectrum of prostanoid action includes effects on immune, endocrine, cardiovascular, renal and reproductive systems as well as the contraction and relaxation of smooth muscle. Accordingly, prostanoids and prostanoid analogues have been used as drugs to treat a variety of clinical conditions, including, but not limited to, conditions associated with the female reproductive system.
One of the clinically important prostanoid receptors is the FP receptor. This receptor is expressed in a range of different species and in a variety of different tissues, including, without limitation, eye, small intestine, corpus luteum, placenta, ovary, brain, myometrium, lung, kidney, stomach, muscle, uterus and trachea, and is particularly prevalent in the corpus luteum, where it mediates luteolysis. Consequently, PGF2α analogues are effective agents for synchronizing the oestrus cycles of a variety of farm animals and have been used to facilitate animal husbandry.
A tissue that has proved useful in the study of the FP receptor is the iris sphincter muscle from both cat and dog. The presence of the FP receptor in ocular tissue has important pharmacological consequences, and PGF2α analogues such as latanoprost have proven effective in lowering intraocular pressure in various species, including humans, where they are used to treat conditions such as glaucoma.
While PGF2α is a potent FP receptor agonist, it is rather non-selective, having appreciable agonist activity at EP and TP receptors. Although analogues of PGF2α have been synthesized that have reduced agonist activity at other prostanoid receptors, the PGF2α agonist drugs currently available still have some agonist activity at other receptors, which can result in undesirable side effects. For example, an ocular side effect of the PGF2α analogue latanoprost is increased iris pigmentation, which is due to increased synthesis of melanin in the melanocytes of the iris stroma. In addition, a low frequency of cystoid macular edema has been reported with this drug, usually in predisposed eyes. Such side effects may be due in part to a lack of receptor specificity.
A goal of clinical pharmacology and the pharmaceutical industry is the development of more selective drugs with greater efficacy and fewer side effects than those currently in use. In order to more effectively treat conditions where FP receptor modulators can be of benefit such as glaucoma, new receptors related to the known wild-type FP receptor must be discovered and used to design screening assays for identification of compounds that bind more specifically to the known FP receptor. Newly identified FP receptors such as alternatively spliced FP receptors can be more closely associated with a disease such as glaucoma than the known FP receptor and can be targets for drug discovery efforts, resulting in the development of drugs having greater efficacy or fewer side effects than drugs developed against the known wild-type FP receptor.
Thus, there exists a need for the discovery of new FP receptors which can be used, for example, to design more specific drugs with fewer side effects. The present invention satisfies this need and provides related advantages as well.